Overcoming treatment resistance in glioblastoma multiforme by tumour specific inhibition of DNA repair.

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Aims
To identify and characterise novel, effective therapies for treating glioblastoma multiforme (GBM) by tumour-specific inhibition of DNA repair.
Objectives
(1) Demonstrate whether inhibitors of DNA repair proteins increase radiosensitivity of human glioma stem cells. (2) In vivo analysis of the effects of PARP inhibitors on DNA repair in GBM and normal tissues, alone and in combination with radiation and/or chemotherapy. Identification of biomarkers predictive of response to PARP inhibitors. (3) Establish whether tumour-specific downregulation of O6-methylguanine methyltransferase (MGMT) by modulation of PI3kinase/mTOR signalling overcomes temozolomide resistance of human glioma cells with unmethylated MGMT gene promoters.
Design and methodology
(1) Analysis of effects of inhibitors of PARP, DNA-PKcs, ATM, Chk1 and Chk2 on radiation responses of human glioma stem cells, measured by clonogenic survival, induction and repair of DNA damage (immunofluorescence and comet assays) and cell cycle parameters. Active agents will be tested in vivo by quantifying effects on tumorigenicity of irradiated glioma stem cells implanted into the forebrains of SCID mice.
(2) Immunohistochemical analysis of induction and repair of DNA double strand breaks, measured by H2AX, 53BP1 and Rad51 foci, in tumour specimens and hair follicles of patients in early phase clinical trials of the PARP inhibitor AZD2281 +/- radiotherapy and/or temozolomide. Dual staining will address cell cycle phase specificity. Repair parameters will be correlated with progression-free and overall survival.
(3) Measurement of effects of inhibitors of p38MAPkinase, mTOR or ERK signalling on MGMT gene and protein expression and temozolomide sensitivity of human glioma cells and glioma stem cells.
Scientific opportunities
Studies on glioma stem cells will verify or refute previous observations that they are radioresistant, and elucidate mechanisms underlying this phenotype. Translational studies using tumour resection specimens will interrogate in vivo effects of PARP inhibitors on DNA repair processes in GBM and normal tissues treated with radiotherapy and chemotherapy. Understanding the mechanisms underlying effects of PI3kinase/mTOR inhibition on MGMT expression will provide novel insights into interactions between oncogenic signalling pathways and protein translation, and elucidate the key factors regulating activity of this DNA repair protein.
Medical opportunities
All aspects of this proposal are aimed at improving treatment of GBM. Overcoming radioresistance of glioma stem cells is likely to be necessary to achieve tumour cure; elucidating mechanisms of sensitisation by PARP inhibitors in vivo and identifying predictive biomarkers will define their therapeutic role; and tumour-specific downregulation of MGMT may improve outcomes in GBM that are resistant to existing therapies.

Publications

10 25 50
 
Description Appointed to Executive Board of the European Association of Neuro-Oncology
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Cancer Research UK Strategic Review of Radiation Biology and Radiation Oncology
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Consensus Statement Drug-Radiotherapy Combinations
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
URL http://www.nature.com/nrclinonc/journal/v13/n10/full/nrclinonc.2016.79.html
 
Description Department of Health Working Group on Brain Tumour Research
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL https://www.gov.uk/government/publications/brain-tumour-research-task-and-finish-working-group-repor...
 
Description Deputy Chair of the Clinical and Translational Radiotherapy Research Working Group (CTRad)
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Organised, hosted, participated in and delivered lectures and presentations in regular Academic Think Tanks, Clinical Trials Proposals Guidance meetings, Clinical Trials Workshops, Topic Based Academic Workshops and Academic Workshops for Clinical Oncology Trainees. Together these activities have increased the number and quality of academic and research active Clinical Oncologists in the UK, increased the number of radiotherapy clinical trials, increased the number of patients recruited into clinical trials and helped to deliver improvements in clinical outcomes and quality of life through successful delivery of these trials.
URL http://ctrad.ncri.org.uk/about-ctrad/ctrad-achievements-and-vision
 
Description Developed and delivered radiobiology training programme for all oncology trainees in Scotland.
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Contributed to the training of the Oncology workforce in the UK. Enabled oncology trainees to pass FRCR exams required to become consultants. Stimulated some trainees to undertake research degrees.
 
Description ESTRO-ACROP guideline "target delineation of glioblastomas"
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
URL http://www.sciencedirect.com/science/article/pii/S0167814015006611
 
Description FRCR exam board member
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Improved knowledge of radiobiology in the Clinical Oncology workforce
 
Description ICR MSc Oncology Module Leader
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Increase in academic clinical oncology personnel in the UK. Increase in radiotherapy clinical trials.
 
Description Increased funding for radiotherapy in Scottish Cancer Strategy
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
URL http://www.gov.scot/Publications/2016/03/9784
 
Description Tessa Jowell Brain Cancer Mission
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description CRUK Bayer Healthcare Drug Discovery Project Award
Amount £200,000 (GBP)
Funding ID C16583/A19438 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 01/2017
 
Description Clinical Trial Grant
Amount £244,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 07/2015 
End 07/2020
 
Description Clinical Trial Grant (PARADIGM)
Amount £328,000 (GBP)
Funding ID C16583/A17870 
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 01/2014 
End 12/2017
 
Description Drug Discovery Project Award
Amount £175,820 (GBP)
Funding ID C16583/A24893 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2018 
End 03/2020
 
Description Glasgow CRUK RadNet Radiation Research Centre of Excellence: 'Treating the untreatable - from mouse to man'
Amount £3,419,387 (GBP)
Funding ID 28803 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2019 
End 10/2024
 
Description MRC Senior Clinical Fellowship
Amount £1,400,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2009 
End 07/2014
 
Description New Agents Committee Preclinical Grant
Amount £49,061 (GBP)
Funding ID C16583/A25411 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2018 
End 06/2019
 
Description Project Award (CSO)
Amount £225,000 (GBP)
Funding ID ETM/405 
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 02/2015 
End 01/2017
 
Description Project Grant
Amount £350,000 (GBP)
Organisation BenevolentAI 
Sector Private
Country United Kingdom
Start 03/2018 
End 02/2021
 
Description Project Grant
Amount £368,203 (GBP)
Funding ID NC/P001335/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2017 
End 01/2020
 
Description Research Grant
Amount £284,000 (GBP)
Organisation AstraZeneca 
Department Astra Zeneca
Sector Private
Country United States
Start 09/2017 
End 09/2020
 
Description Strathclyde Chancellor's Fellow (Lecturer)
Amount £400,000 (GBP)
Organisation University of Strathclyde 
Sector Academic/University
Country United Kingdom
Start 07/2020 
End 07/2025
 
Title Novel 3-dimensional cell culture model of glioblastoma 
Description Created a novel 3D cell culture model of glioblastoma that recapitulates the results of clinical trials whereas conventional 2D cell culture models do not. This new model has proved to be very attractive to pharmaceutical and biotechnology companies who have funded us to use it to evaluate and screen potential novel treatments for glioblastoma. 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2017 
Provided To Others? Yes  
Impact Initial publication in NeuroOncology (cited 72 times): Gomez-Roman N, Stevenson K, Gilmour L, Hamilton G, Chalmers AJ. A novel 3D human glioblastoma cell culture system for modelling drug and radiation responses. Neuro Oncol. 2017 Feb 1;19(2):229-241. Gomez-Roman N, Chong MY, Chahal SK, Caragher SP, Jackson MR, Stevenson KH, Dongre SA, Chalmers AJ. Radiation responses of 2D and 3D glioblastoma cells: a novel, 3D-specific radioprotective role of VEGF/Akt signaling through functional activation of NHEJ. Mol Cancer Ther. 2020 Feb;19(2):575-589. Research grants: 2019-24 Cancer Research UK RadNet Centre of Excellence £3,500,000 Radiotherapy research infrastructure award 2018-21 BenevolentAI Project Grant £350,000 Hypothesis validation for glioblastoma using a 3D GBM model. 2018-20 Cancer Research UK Drug Discovery Project Award £175,820 Evaluating the therapeutic potential of PARG inhibition in glioblastoma and further elucidating the mechanism(s) of action. 2016-19 NC3R Project Grant: £368,203. A 3D in vitro glioblastoma cell culture system for identification and evaluation of novel radiosensitisers reducing rodent xenograft studies. 
URL https://doi.org/10.1093/neuonc/now164
 
Description Clinical trial of olaparib in recurrent glioblastoma 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution I am Chief Investigator and have written the protocol. I oversaw the conduct of the trial and wrote the manuscript.
Collaborator Contribution Approved funding for a phase I clinical trial. The Drug Development Office of CRUK are managing the study, for which I am Chief Investigator. Astra Zeneca has provided drug and performed some assays.
Impact Phase I clinical trial completed. The findings underpinned development of subsequent clinical trials of olaparib plus radiotherapy and/or temozolomide in gliobastoma - PARADIGM and PARADIGM-2. High impact publication: Hanna C, Kurian KM, Williams K, Watts C, Jackson A, Carruthers R, Strathdee K, Cruickshank G, Dunn L, Erridge S, Godfrey L, Jefferies S, McBain C, Sleigh R, McCormick A, Pittman M, Halford S, Chalmers AJ. Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Neuro Oncol. 2020 Dec 18;22(12):1840-1850.
Start Year 2009
 
Description Clinical trial of olaparib in recurrent glioblastoma 
Organisation Cancer Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I am Chief Investigator and have written the protocol. I oversaw the conduct of the trial and wrote the manuscript.
Collaborator Contribution Approved funding for a phase I clinical trial. The Drug Development Office of CRUK are managing the study, for which I am Chief Investigator. Astra Zeneca has provided drug and performed some assays.
Impact Phase I clinical trial completed. The findings underpinned development of subsequent clinical trials of olaparib plus radiotherapy and/or temozolomide in gliobastoma - PARADIGM and PARADIGM-2. High impact publication: Hanna C, Kurian KM, Williams K, Watts C, Jackson A, Carruthers R, Strathdee K, Cruickshank G, Dunn L, Erridge S, Godfrey L, Jefferies S, McBain C, Sleigh R, McCormick A, Pittman M, Halford S, Chalmers AJ. Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Neuro Oncol. 2020 Dec 18;22(12):1840-1850.
Start Year 2009
 
Description Clinical trial of olaparib in recurrent glioblastoma 
Organisation University of Bristol
Department Institute of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I am Chief Investigator and have written the protocol. I oversaw the conduct of the trial and wrote the manuscript.
Collaborator Contribution Approved funding for a phase I clinical trial. The Drug Development Office of CRUK are managing the study, for which I am Chief Investigator. Astra Zeneca has provided drug and performed some assays.
Impact Phase I clinical trial completed. The findings underpinned development of subsequent clinical trials of olaparib plus radiotherapy and/or temozolomide in gliobastoma - PARADIGM and PARADIGM-2. High impact publication: Hanna C, Kurian KM, Williams K, Watts C, Jackson A, Carruthers R, Strathdee K, Cruickshank G, Dunn L, Erridge S, Godfrey L, Jefferies S, McBain C, Sleigh R, McCormick A, Pittman M, Halford S, Chalmers AJ. Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Neuro Oncol. 2020 Dec 18;22(12):1840-1850.
Start Year 2009
 
Description DNA repair signatures as biomarkers of response to radiotherapy-drug combinations in glioblastoma 
Organisation Catalan Institute of Oncology (ICO)
Country Spain 
Sector Public 
PI Contribution Contributed biospecimens, knowledge, scientific and clinical input to this new collaboration, and introduced additional partners. Contributed to grant applications and publications.
Collaborator Contribution Contributed scientific knowledge, data, bioinformatics expertise and pre-clinical models.
Impact High impact publication: Liu Q, Palomero L, Moore J, Guix I, Espín R, Aytés A, Mao JH, Paulovich AG, Whiteaker JR, Ivey RG, Iliakis G, Luo D, Chalmers AJ, Murnane J, Pujana MA, Barcellos-Hoff MH. Loss of TGFß signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types. Sci Transl Med. 2021 Feb 10;13(580):eabc4465. Grant applications submitted but not yet successful.
Start Year 2019
 
Description DNA repair signatures as biomarkers of response to radiotherapy-drug combinations in glioblastoma 
Organisation NYU Langone Medical Center
Country United States 
Sector Academic/University 
PI Contribution Contributed biospecimens, knowledge, scientific and clinical input to this new collaboration, and introduced additional partners. Contributed to grant applications and publications.
Collaborator Contribution Contributed scientific knowledge, data, bioinformatics expertise and pre-clinical models.
Impact High impact publication: Liu Q, Palomero L, Moore J, Guix I, Espín R, Aytés A, Mao JH, Paulovich AG, Whiteaker JR, Ivey RG, Iliakis G, Luo D, Chalmers AJ, Murnane J, Pujana MA, Barcellos-Hoff MH. Loss of TGFß signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types. Sci Transl Med. 2021 Feb 10;13(580):eabc4465. Grant applications submitted but not yet successful.
Start Year 2019
 
Description DNA repair signatures as biomarkers of response to radiotherapy-drug combinations in glioblastoma 
Organisation Queen's University Belfast
Department Centre for Cancer Research and Cell Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributed biospecimens, knowledge, scientific and clinical input to this new collaboration, and introduced additional partners. Contributed to grant applications and publications.
Collaborator Contribution Contributed scientific knowledge, data, bioinformatics expertise and pre-clinical models.
Impact High impact publication: Liu Q, Palomero L, Moore J, Guix I, Espín R, Aytés A, Mao JH, Paulovich AG, Whiteaker JR, Ivey RG, Iliakis G, Luo D, Chalmers AJ, Murnane J, Pujana MA, Barcellos-Hoff MH. Loss of TGFß signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types. Sci Transl Med. 2021 Feb 10;13(580):eabc4465. Grant applications submitted but not yet successful.
Start Year 2019
 
Description DNA repair signatures as biomarkers of response to radiotherapy-drug combinations in glioblastoma 
Organisation University of California, San Francisco
Department School of Medicine (UCSF)
Country United States 
Sector Academic/University 
PI Contribution Contributed biospecimens, knowledge, scientific and clinical input to this new collaboration, and introduced additional partners. Contributed to grant applications and publications.
Collaborator Contribution Contributed scientific knowledge, data, bioinformatics expertise and pre-clinical models.
Impact High impact publication: Liu Q, Palomero L, Moore J, Guix I, Espín R, Aytés A, Mao JH, Paulovich AG, Whiteaker JR, Ivey RG, Iliakis G, Luo D, Chalmers AJ, Murnane J, Pujana MA, Barcellos-Hoff MH. Loss of TGFß signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types. Sci Transl Med. 2021 Feb 10;13(580):eabc4465. Grant applications submitted but not yet successful.
Start Year 2019
 
Description Evaluating adverse effects of radiotherapy-drug combinations on the normal brain 
Organisation University of Manchester
Department Manchester Pharmacy School
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed concept and initiated collaboration. Developed in vitro and in vivo models. Obtained funding for experiments.
Collaborator Contribution Contributed to concept and funding applications. Provided advanced preclinical imaging resources for experiments, and preclincial behavioural expertise and facilities.
Impact 2017-19 AstraZeneca Research Grant £177,741 Understanding the impact of ATM inhibition on radiation-induced normal brain toxicity through imaging, behavioural, histopathological, cellular and molecular studies. 2019 - 21 AstraZeneca Research Grant - extension with additional funding £106,000 Invited presentation at American Association of Cancer Research Virtual Special Conference: Radiation Sciences and Medicine, 1-2 March 2021.
Start Year 2017
 
Description Hypoxia-activated PARP inhibitors 
Organisation Sentinel Oncology
Country United Kingdom 
Sector Private 
PI Contribution Initiated collaboration, jointly developed research concept, wrote grant application to Medical Research Council Fellowship Industry Partnership Award, secured funding and appointed research associate.
Collaborator Contribution Jointly developed research concept, assisted in writing of grant application, provided funding 'in kind' as detailed in application.
Impact Medical Research Council Fellowship Industry Partnership Award
Start Year 2012
 
Description PARADIGM 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Clinical trial design and delivery.
Collaborator Contribution Study funded by AstraZeneca and endorsed by CRUK through CTAAC. Assistance with study design and partnership with AstraZeneca provided by the Combinations Alliance.
Impact Phase I dose escalation of PARADIGM is complete. Randomised phase II component of PARADIGM is underway; 145 patients have been registered and 74 patients randomised. Tissue collection underway.
Start Year 2013
 
Description PARADIGM 
Organisation Cancer Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Clinical trial design and delivery.
Collaborator Contribution Study funded by AstraZeneca and endorsed by CRUK through CTAAC. Assistance with study design and partnership with AstraZeneca provided by the Combinations Alliance.
Impact Phase I dose escalation of PARADIGM is complete. Randomised phase II component of PARADIGM is underway; 145 patients have been registered and 74 patients randomised. Tissue collection underway.
Start Year 2013
 
Description PARADIGM-2 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Clinical trial design and protocol delivery. Translational research design.
Collaborator Contribution Funding from AstraZeneca. Funding and assistance with study design and management of the collaboration with AstraZeneca from CRUK.
Impact Clinical trial protocol complete. Phase I dose escalation complete in parallel 2 (MGMT unmethylated patients); recruitment to dose expansion cohort nearly complete (n=30). Phase I dose escalation underway in parallel 1 (MGMT methylated patients). Translational studies underway (tissue and imaging).
Start Year 2014
 
Description PARADIGM-2 
Organisation Cancer Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Clinical trial design and protocol delivery. Translational research design.
Collaborator Contribution Funding from AstraZeneca. Funding and assistance with study design and management of the collaboration with AstraZeneca from CRUK.
Impact Clinical trial protocol complete. Phase I dose escalation complete in parallel 2 (MGMT unmethylated patients); recruitment to dose expansion cohort nearly complete (n=30). Phase I dose escalation underway in parallel 1 (MGMT methylated patients). Translational studies underway (tissue and imaging).
Start Year 2014
 
Description Radiation and cancer associated fibroblasts 
Organisation University of Tromso
Country Norway 
Sector Academic/University 
PI Contribution Intellectual contribution to project concept, experimental design, data interpretation and manuscript writing.
Collaborator Contribution Intellectual contribution to project concept, conducted experiments, data interpretation, manuscript writing.
Impact Hellevik T, Pettersen I, Berg V, Winberg JO, Moe BT, Bartnes K, Paulssen RH, Busund LT, Bremnes R, Chalmers A, Martinez-Zubiaurre I. Cancer-associated fibroblasts from human NSCLC survive ablative doses of radiation but their invasive capacity is reduced. Radiat Oncol. 2012; 7(1):59. Hellevik T, Pettersen I, Berg V, Bruun J, Bartnes K, Busund LT, Chalmers A, Bremnes R, Martinez-Zubiaurre I. Changes in the Secretory Profile of NSCLC-Associated Fibroblasts after Ablative Radiotherapy: Potential Impact on Angiogenesis and Tumor Growth. Transl Oncol. 2013;6(1):66-74 Martinez-Zubiaurre I, Chalmers AJ, Hellevik T. Radiation-Induced Transformation of Immunoregulatory Networks in the Tumor Stroma. Front Immunol. 2018 Jul 26;9:1679.
Start Year 2011
 
Description Radiological evaluation of adverse effects of radiotherapy on the normal brain 
Organisation Utrecht University
Country Netherlands 
Sector Academic/University 
PI Contribution We are providing imaging and clinical data to enable evaluation of the effects of radiotherapy on the healthy brain of patients with glioblastoma, and subsequent analysis of whether novel inhibitors of the DNA damage response modulate these effects. We also provide scientific and clinical expertise and experience.
Collaborator Contribution Novel image analysis methodologies and pipelines, scientific and bioinformatic expertise.
Impact AstraZeneca has allocated funding from the PARADIGM clincial trial grant to support this collaboration. Disciplines involved include Medical (Clinical Oncology, Neurosurgery, Radiology), Therapy Radiography, Bioinformatics.
Start Year 2021
 
Description UK glioblastoma radiotherapy-drug combinations consortium 
Organisation CTRad
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Based on my previous scientific and clinical research in this field I initiated and am organising and hosting a workshop aimed at developing a multi-centre, multi-arm, multi-stage clinical trial of radiotherapy in combination with various DNA repair inhibitors in the treatment of glioblastoma. The consortium will include clinicians, biological and imaging scientists, pharmaceutical companies, statisticians and consumer representatives.
Collaborator Contribution CTRad supporting workshop expenses and travel for invited speakers. NCRI Brain Tumour CSG supporting workshop administration. Clinical Trials Unit Glasgow supporting workshop administration and future development of the clinical trial.
Impact Workshop taking place in Glasgow on 16-17 March 2017. This collaboration has been absorbed into the Tessa Jowell BRAIN MATRIX clinical trial platform. Anthony Chalmers is responsible for developing radiotherapy-drug combination studies within this platform, which has been fully funded by The Brain Tumour Charity and is due to open in 10 UK centres in 2021.
Start Year 2016
 
Description UK glioblastoma radiotherapy-drug combinations consortium 
Organisation Cancer Research UK
Department Clinical Trials Unit (CTU) Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Based on my previous scientific and clinical research in this field I initiated and am organising and hosting a workshop aimed at developing a multi-centre, multi-arm, multi-stage clinical trial of radiotherapy in combination with various DNA repair inhibitors in the treatment of glioblastoma. The consortium will include clinicians, biological and imaging scientists, pharmaceutical companies, statisticians and consumer representatives.
Collaborator Contribution CTRad supporting workshop expenses and travel for invited speakers. NCRI Brain Tumour CSG supporting workshop administration. Clinical Trials Unit Glasgow supporting workshop administration and future development of the clinical trial.
Impact Workshop taking place in Glasgow on 16-17 March 2017. This collaboration has been absorbed into the Tessa Jowell BRAIN MATRIX clinical trial platform. Anthony Chalmers is responsible for developing radiotherapy-drug combination studies within this platform, which has been fully funded by The Brain Tumour Charity and is due to open in 10 UK centres in 2021.
Start Year 2016
 
Description UK glioblastoma radiotherapy-drug combinations consortium 
Organisation National Cancer Research Institute (NCRI)
Department NCRI Brain Tumour CSG
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Based on my previous scientific and clinical research in this field I initiated and am organising and hosting a workshop aimed at developing a multi-centre, multi-arm, multi-stage clinical trial of radiotherapy in combination with various DNA repair inhibitors in the treatment of glioblastoma. The consortium will include clinicians, biological and imaging scientists, pharmaceutical companies, statisticians and consumer representatives.
Collaborator Contribution CTRad supporting workshop expenses and travel for invited speakers. NCRI Brain Tumour CSG supporting workshop administration. Clinical Trials Unit Glasgow supporting workshop administration and future development of the clinical trial.
Impact Workshop taking place in Glasgow on 16-17 March 2017. This collaboration has been absorbed into the Tessa Jowell BRAIN MATRIX clinical trial platform. Anthony Chalmers is responsible for developing radiotherapy-drug combination studies within this platform, which has been fully funded by The Brain Tumour Charity and is due to open in 10 UK centres in 2021.
Start Year 2016
 
Description UK non-small cell lung cancer radiotherapy-drug combinations consortium 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution I initiated this consortium by recognising the need and organising a two day workshop in Glasgow in February 2016. I chaired the workshop and oversaw the subsequent process that led to the creation of two multi-centre, multi-arm studies of novel radiotherapy-drug combinations for non-small cell lung cancer. I contributed to the design, funding and implementation of the CONCORDE study which arose from this collaboration -see details below.
Collaborator Contribution NCRI Lung Cancer CSG assisted with workshop organisation, and set up a Short Life Working Party to enable the outputs of the workshop to be developed further.
Impact This collaboration has given rise to the CONCORDE trial which is a novel phase I platform study testing up to five different DNA damage response inhibitors in combination with radical radiotherapy for inoperable stage II-III non-small cell lung cancer. The trial has been funded by Cancer Research UK (£900,000) with additional funding from AstraZeneca for each of the study arms. It is due to open in 8 UK sites in 2021. Publications arising from this collaboration: Walls GM, Oughton JB, Chalmers AJ, Brown S, Collinson F, Forster MD, Franks KN, Gilbert A, Hanna GG, Hannaway N, Harrow S, Haswell T, Hiley CT, Hinsley S, Krebs M, Murden G, Phillip R, Ryan AJ, Salem A, Sebag-Montefoire D, Shaw P, Twelves CJ, Walker K, Young RJ, Faivre-Finn C, Greystoke A. CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer. Clin Transl Radiat Oncol. 2020 Sep 22;25:61-66. Harrow S, Hanna GG, Faivre-Finn C, McDonald F, Chalmers AJ. The Challenges Faced in Developing Novel Drug Radiation Combinations in Non-small Cell Lung Cancer. Clin Oncol (R Coll Radiol). 2016 Nov;28(11):720-725.
Start Year 2016
 
Description UK non-small cell lung cancer radiotherapy-drug combinations consortium 
Organisation CTRad
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I initiated this consortium by recognising the need and organising a two day workshop in Glasgow in February 2016. I chaired the workshop and oversaw the subsequent process that led to the creation of two multi-centre, multi-arm studies of novel radiotherapy-drug combinations for non-small cell lung cancer. I contributed to the design, funding and implementation of the CONCORDE study which arose from this collaboration -see details below.
Collaborator Contribution NCRI Lung Cancer CSG assisted with workshop organisation, and set up a Short Life Working Party to enable the outputs of the workshop to be developed further.
Impact This collaboration has given rise to the CONCORDE trial which is a novel phase I platform study testing up to five different DNA damage response inhibitors in combination with radical radiotherapy for inoperable stage II-III non-small cell lung cancer. The trial has been funded by Cancer Research UK (£900,000) with additional funding from AstraZeneca for each of the study arms. It is due to open in 8 UK sites in 2021. Publications arising from this collaboration: Walls GM, Oughton JB, Chalmers AJ, Brown S, Collinson F, Forster MD, Franks KN, Gilbert A, Hanna GG, Hannaway N, Harrow S, Haswell T, Hiley CT, Hinsley S, Krebs M, Murden G, Phillip R, Ryan AJ, Salem A, Sebag-Montefoire D, Shaw P, Twelves CJ, Walker K, Young RJ, Faivre-Finn C, Greystoke A. CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer. Clin Transl Radiat Oncol. 2020 Sep 22;25:61-66. Harrow S, Hanna GG, Faivre-Finn C, McDonald F, Chalmers AJ. The Challenges Faced in Developing Novel Drug Radiation Combinations in Non-small Cell Lung Cancer. Clin Oncol (R Coll Radiol). 2016 Nov;28(11):720-725.
Start Year 2016
 
Description UK non-small cell lung cancer radiotherapy-drug combinations consortium 
Organisation National Cancer Research Institute (NCRI)
Country United Kingdom 
Sector Academic/University 
PI Contribution I initiated this consortium by recognising the need and organising a two day workshop in Glasgow in February 2016. I chaired the workshop and oversaw the subsequent process that led to the creation of two multi-centre, multi-arm studies of novel radiotherapy-drug combinations for non-small cell lung cancer. I contributed to the design, funding and implementation of the CONCORDE study which arose from this collaboration -see details below.
Collaborator Contribution NCRI Lung Cancer CSG assisted with workshop organisation, and set up a Short Life Working Party to enable the outputs of the workshop to be developed further.
Impact This collaboration has given rise to the CONCORDE trial which is a novel phase I platform study testing up to five different DNA damage response inhibitors in combination with radical radiotherapy for inoperable stage II-III non-small cell lung cancer. The trial has been funded by Cancer Research UK (£900,000) with additional funding from AstraZeneca for each of the study arms. It is due to open in 8 UK sites in 2021. Publications arising from this collaboration: Walls GM, Oughton JB, Chalmers AJ, Brown S, Collinson F, Forster MD, Franks KN, Gilbert A, Hanna GG, Hannaway N, Harrow S, Haswell T, Hiley CT, Hinsley S, Krebs M, Murden G, Phillip R, Ryan AJ, Salem A, Sebag-Montefoire D, Shaw P, Twelves CJ, Walker K, Young RJ, Faivre-Finn C, Greystoke A. CONCORDE: A phase I platform study of novel agents in combination with conventional radiotherapy in non-small-cell lung cancer. Clin Transl Radiat Oncol. 2020 Sep 22;25:61-66. Harrow S, Hanna GG, Faivre-Finn C, McDonald F, Chalmers AJ. The Challenges Faced in Developing Novel Drug Radiation Combinations in Non-small Cell Lung Cancer. Clin Oncol (R Coll Radiol). 2016 Nov;28(11):720-725.
Start Year 2016
 
Title Temozolomide and olaparib for recurrent glioblastoma 
Description Phase I evaluation of olaparib and temozolomide in recurrent glioblastoma was completed and the results published in 2020: Hanna C, Kurian KM, Williams K, Watts C, Jackson A, Carruthers R, Strathdee K, Cruickshank G, Dunn L, Erridge S, Godfrey L, Jefferies S, McBain C, Sleigh R, McCormick A, Pittman M, Halford S, Chalmers AJ. Pharmacokinetics, safety and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Neuro Oncol. 2020 Dec 18;22(12):1840-1850. The results of this trial have underpinned ongoing clinical evaluation of olaparib and temozolomide in combination with radiotherapy in patients with newly diagnosed glioblastoma, both in younger patients (PARADIGM-2 trial) and older patients (PARADIGM trial). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2020
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Underpinned development and funding of PARADIGM and PARADIGM-2 clinical trials. 
URL https://academic.oup.com/neuro-oncology/article-lookup/doi/10.1093/neuonc/noaa104
 
Description BNA2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact An oral presentation to 100 audience members entitled 'Optimising chemotherapy and radiotherapy responses of brain tumours - a scientific perspective' in a symposium entitled "Brain tumours: A complex, challenging and under-recognised area of neuroscience".

None to date.
Year(s) Of Engagement Activity 2013
 
Description Brain Tumour Research department visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Third sector organisations
Results and Impact I organised and hosted a visit from the Chief Scientific Officer of Brain Tumour Research to the department at which short talks were given by local brain tumour researchers and a discussion held about gaps in the UK brain tumour research infrastructure and potential funding solutions.
Year(s) Of Engagement Activity 2017
 
Description Brain Tumour Support Group 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Informal presentation on my research and on clinical trials for patients with brain tumours.

None.
Year(s) Of Engagement Activity 2007,2009
 
Description Brain Tumour Support Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 30 patients with brain tumours or relatives attended their monthly support group meeting. I gave an informal talk about my research projects and the clinical trials arising from them.

No measurable impacts.
Year(s) Of Engagement Activity 2008,2010
 
Description Brain Tumour UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact 60 patients, carers, health care professionals and charity workers attended a presentation and discussion as part of the Brain Tumour UK Annual Conference in Glasgow.

Patients and charity workers contacted me for information about clinical trials.
Year(s) Of Engagement Activity 2011
 
Description CRUK Open Evening 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 120 members of the public attended an open evening, including CUK fundraisers, school children, patients. I gave a 20 minute talk on radiotherapy research.

No specific impacts recorded.
Year(s) Of Engagement Activity 2012
 
Description Delivered the biannual Royal College of Radiologists Public Lecture in June 2019. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I delivered the biannual Royal College of Radiologists biannual Public Lecture on the topic: Targeting cancer through new radiotherapy-drug combinations. The lecture was attended by 50 people in person with additional remote viewers. The lecture was filmed and posted online where it has been viewed 300 times.
Year(s) Of Engagement Activity 2019
URL https://www.rcr.ac.uk/discover-and-explore/rcr-talks/targeting-cancer-through-new-radiotherapy-drug-...
 
Description ESTRO Pre-Meeting Radiobiology Course 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Organised and gave an oral presentation during a one-day workshop entitled 'Clinical applications of new combinations: how to test and optimise novel biological agents in combination with radiotherapy'. Facilitated discussions during the workshop.
Year(s) Of Engagement Activity 2016
 
Description Invited speaker ESTRO 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker on the topic: DNA damage response inhibitor combinations in 2019: are we any closer to clinical benefit? as part of a symposium at the 2019 ESTRO conference.
Year(s) Of Engagement Activity 2019
 
Description Invited speaker National Cancer Research Institute Cancer Conference November 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact 25 minute presentation on new models of glioblastoma for preclinical research
Year(s) Of Engagement Activity 2018
 
Description Invited speaker at British Neuro-Oncology Society 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave an oral presentation entitled 'Targeting glioblastoma stem cells in clinical studies' as part of the Education Day at the British Neuro-Oncology Society, Leeds, 2016
Year(s) Of Engagement Activity 2016
 
Description Invited speaker at European Association of Neuro-Oncology conference 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Delivered an oral presentation entitled 'Precision radiation oncology' as part of a special session jointly organised by EANO, SNO and ASNO as part of the European Association of Neuro-Oncology biannual conference.
Year(s) Of Engagement Activity 2016
 
Description Invited speaker at NCRI Cancer Conference 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave an oral presentation entitled 'Why don't drug companies provide access to drugs for use in combination with radiotherapy?' as part of a radiotherapy symposium at the 2016 NCRI Cancer Conference, and participated in a subsequent Q&A session.
Year(s) Of Engagement Activity 2016
 
Description Invited speaker at UK Radiation Oncology conference 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave an oral presentation entitled 'Combining radiotherapy with DNA damage and repair inhibitors' and participated in a Q&A session.
Year(s) Of Engagement Activity 2016
 
Description Invited speaker at conference on Phase I Clinical Trials in Cancer 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact As an invited speaker I gave a presentation on the topic: Combining radiotherapy with inhibitors of the DNA damage response: are conventional phase I trials giving us the data we need? and then participated in a Q&A session with the other speakers.
Year(s) Of Engagement Activity 2019
URL http://www.mcrc.manchester.ac.uk/Conference
 
Description Invited speaker for 'How to be a department head' session at ESTRO Conference 2020 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to give a presentation on 'How to be a department head' at a special session for young ESTRO members at the ESTRO conference 2020. There was a lot of debate and questions and the session was featured in a subsequent article for the ESTRO newsletter.
Year(s) Of Engagement Activity 2020
 
Description Invited speaker, Tesaro DNA damage response workshop 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Invited speaker at a workshop on DNA damage response inhibitors organised by Tesaro. Triggered discussions over a potential new research collaboration with Tesaro.
Year(s) Of Engagement Activity 2018
URL http://www.theacp.org.uk/userfiles/file/calendar/2018/ngs-ddr-course-october-2018-final.pdf
 
Description Keynote speaker - Dutch National Radiation Oncology and Radiation Biology Society March 2022 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote lecture to 200 clinical and scientific researchers entitled: 'Combining radiotherapy with inhibitors of the DNA damage response - from the lab to the clinic and back again.'
Year(s) Of Engagement Activity 2022
URL https://nvrb.org/meetings/
 
Description Keynote speaker - National Oncology Trainees Collaborative for Healthcare Research Symposium 2022 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I delivered the keynote lecture entitled 'Building a research career in oncology' to 60 medical and clincial oncology trainees and then engaged in a Q&A session with them.
Year(s) Of Engagement Activity 2022
URL https://www.uknotch.com/
 
Description Presentation at launch meeting of Tessa Jowell Brain Cancer Mission 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation on Clinical Trials and Treatments for the launch event of the Tessa Jowell Brain Cancer Mission
Year(s) Of Engagement Activity 2018
 
Description Presentation to All Party Parliamentary Group on Brain Tumours Feb 2022 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact I gave a presentation entitled 'The brain tumour research landscape - what are the gaps?' to MPs, Civil Servants and charities as part of the First Oral Evidence session of the All Party Parliamentary Group on Brain Tumours.
Year(s) Of Engagement Activity 2022
URL https://www.parallelparliament.co.uk/APPG/brain-tumours
 
Description Samantha Dickson Brain Tumour Trust 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact 40 patients, carers and associated members of the public attended a presentation and subsequent discussion on new treatments for brain tumours, as part of the Samantha Dickson Brain Tumour Trust Patient Information Day in Glasgow.

Patients contacted me for information about clinical trials.
Year(s) Of Engagement Activity 2011
 
Description The Brain Tumour Charity department visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Four members of my laboratory (including myself) presented previous and ongoing research findings to other members of the Institute of Cancer Sciences and the CRUK Beatson Institute and to the Chief Scientific Officer of The Brain Tumour Charity. New collaborations were formed and potential funding opportunities highlighted.
Year(s) Of Engagement Activity 2016
 
Description invited speaker AACR Special Conference Radiation Medicine 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker on DNA repair inhibitors in gliolastoma for an AACR Special Conference on Radiation Medicine. There were 271 delegates.
Year(s) Of Engagement Activity 2021